Different inbred strains of mice develop either of two divergent patterns of infection with Leishmania major. Most strains develop healing infections whereas certain strains, such as the BALB/c, develop progressive non-healing disease. The development of resistance to infection occurs when the Th1 subset of CD4plus T cells is activated, while progressive disease occurs in mice in which the Th2 subset of CD4plus is preferentially induced. Although patterns of Th1 or Th2 cell predominance become well established early during infection in specific strains of mice, these patterns are not irreversible since a variety of immunological interventions, including treatment with IL-12 or antibodies to IL-2 and IL-4, will reverse the expected course of disease and immunological phenotype, especially if they are administered at or near the time of infection. These immunological interventions function to influence the initial stages of T cell activation from naive CD4plus cells into full differentiated Th1 or Th2 cells, rather than alter the phenotype of an established response. However, neither IL-12 nor anti-IL-4 treatment, alone, will induce healing in mice with established Th2 type responses. Our laboratory has examined ways to reverse established patterns of Th2 cell predominance in mice with non- healing infections and has shown that immunological interventions designed to either suppress Th2 type responses (anti-IL-4 therapy) or enhance Th1 type responses (IL-12 therapy) will promote healing and resistance in susceptible strains of mice if combined with anti- parasite drug therapy to reduce in vivo levels or parasitization. This proposal will examine how differing levels of infection influence the perpetuation of established populations of Th2 cells or the activation of protective Th1 cells and how drug treatment functions to promote successful immunotherapy. In addition, the source of newly derived populations of Th1 cells and the fate of Th2 type populations will e investigated in mice induced to switch from a Th2 to Th1 type response. Finally, the cellular and biochemical events induced by differing immunotherapeutic protocols will be examined in mice exhibiting varying degrees of polarization toward a Th1 or Th2 type response. These studies should provide a better understanding of how mice with chronic infections respond to therapeutic intervention and provide valuable insight into the development of more innovative treatment regimes for leishmaniasis and other infectious diseases.